Outcome evaluation of the p drivers Program: Randomised controlled trial of a program to improve safe driving among novice drivers.

BACKGROUND: Globally, road traffic crashes are the leading cause of death for young adults. The P Drivers Project was a trial of a behavioural change program developed for, and targeted at, young Australian drivers in their initial months of solo driving when crash risk is at its highest. METHODS: In a parallel group randomised controlled trial, drivers (N = 35,109) were recruited within 100 days of obtaining their probationary licence (allowing them to drive unaccompanied) and randomised to an intervention or control group. The intervention was a 3 to 6-week multi-stage driving behaviour change program (P Drivers Program). Surveys were administered at three time points (pre-Program, approximately one month post-Program and at 12 months after). The outcome evaluation employed an on-treatment analysis comprising the 2,419 intervention and 2,810 control participants who completed all required activities, comparing self-reported crashes and police-reported casualty crashes (primary outcome), infringements, self-reported attitudes and behaviours (secondary outcomes) between groups. RESULTS: The P Drivers Program improved awareness of crash risk factors and intentions to drive more safely, relative to the controls; effects were maintained after 12-months. However, the Program did not reduce self-reported crashes or police-reported casualty crashes. In addition, self-reported violations, errors and risky driving behaviours increased in the intervention group compared to the control group as did recorded traffic infringements. This suggests that despite the Program increasing awareness of risky behaviour in novice drivers, behaviour did not improve. This reinforces the need to collect objective measures to accompany self-reported behaviour and intentions. CONCLUSIONS: The P Drivers Program was successful in improving attitudes toward driving safety but the negative impact on behaviour, lack of effect on crashes, and the large loss to follow-up fail to support the use of a post-licensing behaviour change program to improve novice driver behaviour and reduce crashes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: 363,293 (ANZCTR, 2012).

A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies.

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.

A British Society for haematology guideline: diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.

Social comparisons on social media: online appearance-related activity and body dissatisfaction in adolescent girls.

INTRODUCTION: Adolescents' engagement with online social networking platforms is advancing at an exponential rate and research is needed to investigate any impact on young users' mental health. This study examined appearance-related activity (e.g. looking at photos of friends) on social media and body dissatisfaction among adolescent girls. METHODS: Self-report measures of online appearance-related activity, social comparisons to female target groups, internalization of the thin ideal, body dissatisfaction, and self-esteem were administered to 210 girls (mean age = 15.16 years). RESULTS: Body dissatisfaction was significantly related to (i) time spent engaged in social comparisons and (ii) upward social comparisons with various female targets while online. Evaluating oneself less favorably than the target group of close friends was most strongly associated with poorer body image appraisals. Serial multiple mediation analysis revealed that even after controlling for age and self-esteem, time spent engaged in social comparisons significantly mediated the relationship between online appearance-related activity and body dissatisfaction. This association was then further partially mediated by internalization of the thin ideal, which significantly mediated the relationship between time engaged in social comparisons and body dissatisfaction. DISCUSSION: Results are discussed in terms of online social media platforms representing an additional appearance culture environment for adolescent girls. The effects of this on the mental health of vulnerable users and how future research should investigate protective factors that may buffer young girls from the adverse effects of social media are considered.

Advances in the management of TTP.

Thrombotic thrombocytopenic purpura is an acute life-threatening disorder, associated with a mortality of 90% if unrecognised and untreated. The hallmark is thrombocytopenia and microangiopathic hemolytic anemia, with a blood film characterised by fragmented red cells and end organ damage. The mainstay of treatment is ADAMTS13 replacement, currently with plasma exchange (PEX) and immunosuppression. High dose steroids are used from presentation and anti-CD20 monoclonal antibody therapy, specifically rituximab, is initiated early in the acute disease pathway. The use of the nanobody caplacizumab on confirmation of TTP, by severe ADAMTS13 deficiency (<10iu/dL), has revolutionised acute patient care. Caplacizumab binds the A1 domain, the site on VWF normally occupied by platelets. This results in a quicker normalisation of the platelet count, prevention of exacerbations and refractory disease, reduced PEX and inpatient stay. There is a significant risk of relapse and monitoring of patients allows prophylactic rituximab to be given to prevent further acute admissions.

The largest prison outbreak of TB in Western Europe investigated using whole-genome sequencing.

BACKGROUND: In March 2011, the Department of Public Health East in Ireland were notified of two cases of TB in two prisoners sharing a cell. We define the resulting outbreak and highlight the role of public health and laboratory-based molecular epidemiology in mapping and control of a prison outbreak.METHODS: Cases were identified through clinical presentation, contact tracing, case-finding exercise or enhanced laboratory surveillance. Mycobacterium tuberculosis isolates were genotyped and underwent whole-genome sequencing (WGS).RESULTS: Of the 34 cases of TB linked to the outbreak, 27 were prisoners (79%), 4 prison officers (12%) and 3 community cases (9%). M. tuberculosis was isolated from 31 cases (culture positivity: 91%). A maximum of six single-nucleotide polymorphisms separated the isolates, with 22 being identical, suggestive of a highly infectious 'super-spreader´ within the prison. Isolates belonged to the Beijing sub-lineage, and were susceptible to first-line anti-TB agents. A case-finding exercise incidentally detected a prisoner with multidrug-resistant TB. Of the 143 prison officers screened, 52% had latent TB infection. Litigation costs exceeded five million euros.CONCLUSION: This constitutes the largest prison outbreak of TB in Western Europe investigated using WGS. A robust prison entry TB screening and education programme is required to effect better TB control, and prevent future outbreaks and attendant litigation.

Compact X-ray laser amplifier in the "Water Window".

Spectroscopy and microscopy in the so-called "water-window" is a holy grail of modern molecular biology. A pulsed source of coherent X-rays within this spectral window, falling between 2.3 nm and 4.4 nm, provides a unique tool for time-resolved imaging of bio-systems in their naturally water-rich state. Within this spectral range, water is mostly transparent, while proteins are mostly opaque. This results in a high-contrast image on the sub-cellular level. Here we present, for the first time, generation of a very high gain of G≈ 60/cm in He-like CV ions via transitions to the ground state at 4.03 nm in a table-top device.

Response of tertiary addictions services to opioid dependence during the COVID-19 pandemic.

The emergence of the COVID-19 pandemic has presented the addiction services with an unprecedented set of challenges. Opioid users are particularly vulnerable because of their high level of pre-existing health problems and lifestyle factors. In order to minimise their risks to self and to others in the current Covid-19 crisis, addiction services sought to urgently identify vulnerable individuals, and induct them into opioid substitution treatment (OST) promptly. Additionally, several guidelines were created and regularly updated by the health and safety executive (HSE) for any healthcare staff working with opioid users. These include guidance documents, to facilitate prompt induction of patients onto the OST programme, the prescribing of naloxone to all patients at risk of overdose, eConsultation, medication management for those in self-isolation, and the delivery of injecting equipment. The guidance documents and resources will provide a template for a new way of working for the sector during these challenging times and into the future.

How I treat microangiopathic hemolytic anemia in patients with cancer.

Microangiopathic hemolytic anemia (MAHA) with thrombocytopenia, suggests a thrombotic microangiopathy (TMA), linked with thrombus formation affecting small or larger vessels. In cancer patients, it may be directly related to the underlying malignancy (initial presentation or progressive disease), to its treatment, or a separate incidental diagnosis. It is vital to differentiate incidental thrombotic thrombocytopenia purpura or atypical hemolytic uremic syndrome in cancer patients presenting with a TMA, as they have different treatment strategies, and prompt initiation of treatment impacts outcome. In the oncology patient, widespread microvascular metastases or extensive bone marrow involvement can cause MAHA and thrombocytopenia. A disseminated intravascular coagulation (DIC) picture may be precipitated by sepsis or driven by the cancer itself. Cancer therapies may cause a TMA, either dose-dependent toxicity, or an idiosyncratic immune-mediated reaction due to drug-dependent antibodies. Many causes of TMA seen in the oncology patient do not respond to plasma exchange and, where feasible, treatment of the underlying malignancy is important in controlling both cancer-TMA or DIC driven disease. Drug-induced TMA should be considered and any putative causal agent stopped. We will discuss the differential diagnosis and treatment of MAHA in patients with cancer using clinical cases to highlight management principles.

Laboratory biomarkers associated with COVID-19 severity and management.

The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokines implicated in COVID-19 for their potential application as biomarkers of disease severity, respiratory failure and need of higher-level care. From analysis of 203 samples, CRP, IL-6, IL-10 and LDH were most strongly correlated with the WHO ordinal scale of illness severity, the fraction of inspired oxygen delivery, radiological evidence of ARDS and level of respiratory support (p ≤ 0.001). IL-6 levels of ≥3.27 pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for a requirement of ventilation, and a CRP of ≥37 mg/l of 0.91 and 0.66. Reliable stratification of high-risk cases has significant implications on patient triage, resource management and potentially the initiation of novel therapies in severe patients.

Women and inherited bleeding disorders - A review with a focus on key challenges for 2019.

The area of women and inherited bleeding disorders has undergone quick expansion in recent years. More patients are being identified and expertise to diagnose and manage these patients is now essential for practising physicians. Programs to help educate and empower patients and caregivers are now in place. Common inherited bleeding disorders affecting women include von Willebrand disease (VWD), inherited platelet disorders, and rare inherited bleeding disorders such as factor VII (FVII) deficiency and factor XI (FXI) deficiency. Specific clinical tools have been developed to help clinicians and patients screen for the presence of these bleeding disorders in both adult and pediatric populations. Affected women can experience heavy menstrual bleeding and resulting iron deficiency anemia, postpartum hemorrhage, and hemorrhagic ovarian cysts which need to be properly managed. Excessive bleeding can adversely affect quality of life in these women. Front line therapy for bleeding in mild cases focuses on the use of non-specific hemostatic agents such as DDAVP ®, tranexamic acid and hormonal agents but specific factor replacement and/or blood products may be required in more severe cases, in severe bleeding or as second line treatment when bleeding is not responsive to first line agents. Iron status should be optimised in these women especially in pregnancy and use of an electronic app can now help clinicians achieve this. These patients should ideally be managed by a multidisciplinary team whenever possible even remotely. Although clinical research has closed some knowledge gaps regarding the diagnosis and management of these women, there remains significant variation in practise and lack of evidence-based guidelines still exists in many spheres of clinical care in which caregivers must rely on expert opinion. Ongoing efforts in education and research will continue to improve care for these women and restore quality of life for them.

Beam Focusing and Reduction of Quantum Uncertainty in Width at the Few-Photon Level via Multi-Spatial-Mode Squeezing.

We show for the first time that it is possible to realize laser beam focusing at the few-photon level in the four-wave-mixing process, and at the same time reduce the quantum uncertainty in width. The reduction in quantum uncertainty results directly from the strong suppression of local intensity fluctuations. This surprising effect of simultaneous focusing and reduction of width uncertainty is enabled by multi-spatial-mode (MSM) squeezing, and is not possible via any classical optical approach or single-spatial-mode squeezing. Our results open promising possibilities for quantum-enhanced imaging and metrology; as an example, the limit on the measurement of very small beam displacement can be enhanced within feasible experimental parameters because of beam focusing and the noiseless amplification in the MSM squeezing process.

Pharmacokinetics of plasma infusion in congenital thrombotic thrombocytopenic purpura.

Essentials Congenital thrombotic thrombocytopenic purpura (TTP) is primarily treated with plasma infusion. We present a pharmacokinetic analysis of ADAMTS-13 in six patients following plasma infusion. A median half-life of 130 h was demonstrated, ranging between 82.6 and 189.5 h. Investigation of interindividual clearance of ADAMTS-13 is necessary to optimize treatment. SUMMARY: Background Congenital thrombotic thrombocytopenic purpura (TTP) is defined by persistent severe deficiency of ADAMTS-13 in the absence of anti-ADAMTS-13 inhibitory antibodies, confirmed by mutational analysis. Replacement of the missing protease prevents disease relapse, primarily using plasma infusion (PI). Objectives, patients and methods There is scant evidence regarding optimal dose and frequency of treatment, which tends to be empirically guided. We present a pharmacokinetic analysis of ADAMTS-13 in six patients with congenital TTP on established regimes following PI. Results We found a median clearance of 25.41 mL h-1 and half-life of 130 h, ranging between 82.6 and 189.5 h (3.4-7.9 days, respectively). All patients reached baseline ADAMTS-13 level within 7-10 days post-plasma. Median ADAMTS-13 activity peak post-PI was 24.05 IU dL-1 . Variation was related to elimination rate, which, in turn, was affected by weight and metabolism, but not to von Willebrand factor antigen or activity levels. Using the pharmacokinetic parameters, we simulated individualized protocols based on PI dose or frequency to target hypothetical optimal plasma levels of ADAMTS-13 of 10 and 50 IU dL-1 , respectively. Results suggest a target trough ADAMTS-13 of 10 IU dL-1 is feasible but 50 IU dL-1 would not be achievable taking into account volume required. Conclusions Further work is needed to compare treatment of congenital TTP with PI vs. recombinant ADAMTS-13. PI may provide longer duration of ADAMTS-13 effect, but is limited by plasma volume required, whereas recombinant therapy can provide a higher ADAMTS-13 peak. We propose that investigation of interindividual clearance of ADAMTS-13 is necessary to optimize treatment and provide the rationale for dose and frequency of prophylaxis.

Magnetism in semiconducting molybdenum dichalcogenides.

Transition metal dichalcogenides (TMDs) are interesting for understanding the fundamental physics of two-dimensional (2D) materials as well as for applications to many emerging technologies, including spin electronics. Here, we report the discovery of long-range magnetic order below T M = 40 and 100 K in bulk semiconducting TMDs 2H-MoTe2 and 2H-MoSe2, respectively, by means of muon spin rotation (µSR), scanning tunneling microscopy (STM), and density functional theory (DFT) calculations. The µSR measurements show the presence of large and homogeneous internal magnetic fields at low temperatures in both compounds indicative of long-range magnetic order. DFT calculations show that this magnetism is promoted by the presence of defects in the crystal. The STM measurements show that the vast majority of defects in these materials are metal vacancies and chalcogen-metal antisites, which are randomly distributed in the lattice at the subpercent level. DFT indicates that the antisite defects are magnetic with a magnetic moment in the range of 0.9 to 2.8 µB. Further, we find that the magnetic order stabilized in 2H-MoTe2 and 2H-MoSe2 is highly sensitive to hydrostatic pressure. These observations establish 2H-MoTe2 and 2H-MoSe2 as a new class of magnetic semiconductors and open a path to studying the interplay of 2D physics and magnetism in these interesting semiconductors.

The role of ADAMTS-13 in the coagulopathy of sepsis.

The interaction between platelets and the vessel wall is mediated by various receptors and adhesive proteins, of which von Willebrand factor (VWF) is the most prominent. The multimeric size of VWF is an important determinant of a more intense platelet-vessel wall interaction, and is regulated by the VWF-cleaving protease ADAMTS-13. A deficiency in ADAMTS-13 leads to higher concentrations of ultralarge VWF multimers and pathological platelet-vessel wall interactions, in its most typical and extreme form leading to thrombocytopenic thrombotic purpura, a thrombotic microangiopathy characterized by thrombocytopenia, non-immune hemolysis, and organ dysfunction. Thrombotic microangiopathy associated with low levels of ADAMTS-13 may be a component of the coagulopathy observed in patients with sepsis. Here, we review the potential role of ADAMTS-13 deficiency and ultralarge VWF multimers in sepsis, and their relationship with sepsis severity and prognosis. In addition, we discuss the possible benefit of restoring ADAMTS-13 levels or reducing the effect of ultralarge VWF as an adjunctive treatment in patients with sepsis.

Multiple centre evaluation study of ADAMTS13 activity and inhibitor assays.

INTRODUCTION: Accurate evaluation of ADAMTS13 activity is required for the diagnosis and clinical management of thrombotic microangiopathies, and commercial kits are available for routine laboratory use. METHODS: Our study compares the results from Technoclone (Technoclone GmbH, Austria) activity and Inhibitor kits with specialist laboratory reference methods (FRETS and ELISA IgG) and the impact of transporting frozen samples and comparison of results. RESULTS: This multicentre study identified differences in Technoclone activity results compared to specialist testing, which could potentially impact diagnosis. A change in the commercial kit during the study period appears to have rectified the detection levels. Frozen samples provided comparable results between sites. CONCLUSION: With close attention to normal ranges, commercial kits are suitable for use in the clinical diagnosis of thrombotic microangiopathies and frozen transportation of samples between sites is a suitable approach. However, a robust external quality control system is essential to provide an independent evaluation of changes in kit production.

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura.

Essentials Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality. Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was studied. Fewer caplacizumab-treated patients had a major TE event, an exacerbation, or died versus placebo. Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP. SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti-von Willebrand factor Nanobody® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment. Objective The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura-related death during the study. Methods The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for 'embolic and thrombotic events' was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo. Results Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo-treated patients died from aTTP during the study. Conclusion In total, 11.4% of caplacizumab-treated patients and 43.2% of placebo-treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP.

Amplitude concentration in a phase-modulated spectrum due to femtosecond filamentation.

We present a method by which the spectral intensity of an ultrafast laser pulse can be accumulated at selected frequencies by a controllable amount. Using a 4-f pulse shaper we modulate the phase of the frequency components of a femtosecond laser. By inducing femtosecond filamentation with the modulated pulse, we can concentrate the spectral amplitude of the pulse at various frequencies. The phase mask applied by the pulse shaper determines the frequencies for which accumulation occurs, as well as the intensity of the spectral concentration. This technique provides a way to obtain pulses with adjustable amplitude using only phase modulation and the nonlinear response of a medium. This provides a means whereby information which is encoded into spectral phase jumps may be decoded into measurable spectral intensity spikes.

Retrospective comparative analysis of cardiovascular implantable electronic device infections with and without the use of antibacterial envelopes.

BACKGROUND: Cardiovascular implantable electronic device (CIED) infections are associated with morbidity and mortality. Peri-operative systemic intravenous antibiotic prophylaxis reduces the rate of CIED infections. AIGISRx, a polymer envelope implanted with the CIED, releases minocycline and rifampin, and has been introduced to reduce infections. METHODS: Retrospective review of 184 patients who underwent CIED implantation was conducted. Ninety-two patients were implanted with an AIGISRx envelope (AIGISRx group) and 92 patients were not implanted with an AIGISRx envelope (control group). Data were collected on demographics and risk factors for CIED infections (i.e. congestive heart failure, renal insufficiency, chronic kidney disease, oral anticoagulant use, chronic steroid use, need for lead replacement or revision, temporary pacing, early re-intervention, and having more than two leads in place). Rates of implantation success, major infections and mortality were compared between the AIGISRx group and the control group. RESULTS: The AIGISRx group had longer hospitalizations (6.8±10.7 days vs 3.1±5.2 days; P=0.001), higher chronic corticosteroid use, higher rates of replacement or revision (51.1% vs 8.7%; P=0.001), and a greater proportion of devices with more than two intracardiac leads (42.4% vs 29.3%; P=0.03) than the control group. Successful implantation occurred in 97% of patients in both groups. Major infection was seen in 5.4% of cases in the AIGISRx group and 1.1% of cases in the control group (P=0.048). Device removal was conducted in 3.3% of cases in the AIGISRx group compared with 1.1% of cases in the control group (P=0.16). There were two deaths in the AIGISRx group. Organisms cultured were meticillin-resistant Staphylococcus aureus, meticillin-susceptible S. aureus and Enterococcus faecalis. CONCLUSION: The AIGISRx group had higher rates of major infection but also higher risk factors compared with the control group. The rate of device extraction and CIED-related mortality was higher in the AIGISRx group than in the control group.